NOTES
September 1969 verted to the methiodide salt as above, mp 195-196". Anal. ( C d z 3 ~ z O z I C, ) H. l-Methyl-4-(3-thienyI)-4-hydroxypiperidine( 6 ) was prepared iit !)Of yirlrl acwrditig lo tlie method dcwibed for 5 iisiiig 0.14 mole of "freshly p r e p a k l :Mhienyllithiurn a i d 0.14 niole'*of 2. For microanalysis 6 was converted to the corresponding benzyl bromide salt in THF. Thc solid rnat,crial wa.s washed several times with absoliite EtOII, nip 244-246". *trial. (C17IIzJ3rNOS) C, H , N. l-Methyl-4-(3-thienyl)-4-propionoxypiperidine(8) was obtained by treatment of 6 with 3 equiv of propionyl chloride. For microanalysis 8 was convert,ed to the corresponding benzyl bromide salt. Anal. (CZOH2~BrKOzS) C, H, N. Biological Data.--Using the mouse hot plate method, 7 had an ED60 of 16.0 mg/kg. The onset peak and duration are respectively 3.4, 26.1, and 151.2 min. Compound 8 had a n ED60 of 3.9 mg/kg as compared with 1.3for morphine and 7.5 for codeine. These results suggest t'hat forces other than hydrophobic or van der Waal's are operative.
Acknowledgment.-The authors would like t'o express sincere appreciation and gratit'ude to Dr. Everette L. May for performing the biological tests on these compounds. This work was supported by Grant CA7031 of the Sational Cancer Inst'itute, U. S. Public Health Service.
The Biochemorphology of Cyclobutanecarboximides KARIMULLAH A. ZIRVI AND CHARLES H. JARBOE Medicinal Chemistry Section, Department of Pharmacology, School of Jf edicine, University of Louisville, Louisville, Kentucky gosoa Received January 2'0, 1969
We have shown several imides of cyclobutanecarboxylic acid to have sedative and hypnotic properties.' The effects appear to be structure related since cyclobutanecarboxamide, a variety of small ring imides, and several imides of cyclobutane-1,l-dicarboxylicacid2 are essentially inactive. To better ascertain the biochemorphology of the cyclobutanecarboximides we have synthesized and evaluated the imides in Table I. They were produced using either the reaction of cyclobutanecarboxamide with excess acetylating agent or amide acylation with cyclobutanecarbonyl chloride in pyridine. The compounds comprise related series. Their biological activity has been correlated with molecular structure, water solubility, and partition coefficients. They have been evaluated for general CXS depressant properties, barbiturate potentiation, myorelaxant, antitremorine, and anticonvulsant potency. Experimental Section Chemical Methods.-Elemental analyses were performed by ;\lidwest Microlab, Inc., Indianapolis, Ind. Where analyses are indicated by elemental symbols only, analytical results obtained for those elements were within 1 0 . 4 7 , of theoretical values. N-Formylcyclobutanecarboxamide. Method A.-A solution of 0.4 g (0.009 mole) of formamide, and 10 ml of neutral alumina treated and KOH-dried pyridine was cooled in an ice bath. Cyclobutanecarbonyl chloride, 1 g (0.009 mole), was added with stirring. An exothermic reaction ensued. When it subsided the mixture wm heated on a steam bath for 1 hr and poured into 100 g of crushed ice. The soluble product was separated by bringing (1) R. T.Buckler and C.H. Jarboe. J . Med. C h e n . . 9, 768 (1906). (2) K.A. Zirvi and C. H. Jarhoe, ibid., 11, 183 (1968).
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the solut,ion to p H 3 with 1 X HC1 and extracting with two 50-ml fractions of CHCL. Evaporation of the solvent after NazSOI drying gave N-formylcyclobutanecarboxamide which was crysInllized from pelitniic to yield 0.5 g (40';;) of prodiict, nip !IOo. . i d . IC&NOj) N. N-Caproylcyclobutanecarboxamide. hlethod B.-('ydol)iitattecarboxrtmidc 10.89 g, 0.009 niolc) wan dissolved i l l X i n 1 of pyridine trcatcd as :ttNJVC>, by Iicaiiitg O I I a slcani bath for I5 miu. To this 1.6 g (0.000 inole) of caproyl chloride was added with stirring and cooling. After the vigorous reaction ceased, the mixture was heat'ed for 1 hr on a steam bath and poured over 100 g of crushed ice. The product was filtered, dried, and crystallized from pentane to yield 1.02 g (50%) of imide, mp 65'. Anal. (CnHzaNO2) N. Solubility.-An excess of imide was shaken for 2 hr a t 25' with 20 ml of distilled H$J a t 200 oscillations/min. The suspensions were filtered and the filtrates were analyzed for imide by iiv spectrophotometry using the Amax at 260 mp. Partition Coefficients.-The system 1-octanol-glass-distilled HzO was used. The H& phase was presatiirated with 1-octanol. The l-oct,anol was washed with 6 S HZSO4, 6 S NaOH, and glassdistilled HzO until the aqueoiis phase was neiitral. The imide (40 mg) was dissolved in 20 ml of 1-octanol, aiid the solution was mixed with 200 ml of glass-distilled HzO a t 25' and shaken for 1.5 hr as above. The phases were separated and the HgO layer was centrifuged for 1.5 hr a t 2500 rpm. -Uv spectroscopy, as above, was used to determine the imide in the H2O phase; imide content of the 1-octanol layer was determined by difference. Data are expressed as ratios of 1-octanol content!HzO content. Pharmacological Methods.-In all of the following, mice were used once. They were previously untreated with any drug and permitted to feed ad libidum. Bioassay for Sedative and Hypnotic Properties.-The depressant activity of the compoiinds was determined by observing their effects on the spontaneous activity and righting reflex of virgin female, Swiss-Webster mice neighing 18-22 g. When the righting reflex was lost, a sleeping time determination was made. On oral administration, the compounds were given either as a solution or suspension in 0.2-0.4 ml of lyG gum t,ragacanth using a blunted and bent 18-gauge hypodermic needle feeding tube. On intraperitoneal administration the compounds were given as solutions or suspensions in 0.25% methylcellulose sterile vehicle. The volume of administered solution was 0.2-0.4 ml. I n all experiments the control animals received vehicle. For each dose four control and four test mice were iised. Barbiturate Potentiation.-;\Iice, as above, weighiiig IS-30 g were used and the test sitbstances were admitristered orally aiid intraperit,oneally as above. Petitobarbital sodium (30 nig/kg) was administered 30 miri after the test drug. All soliltions were adjusted so that 0.2-0.4 ml was iised. For each test and each control experiment. five mice were used. One-way analysis of variance tests were run to determine the significance of differences between test group mean sleeping times and their respective controls. For all experiments with probabilities
